Sodium Hydroxide → HCID 178436355, compound

HRID 2367128Notes

Reaction equation

HRID 2367128 reaction equation
[NH2:1][C:2]1[CH:3]=[C:4]([C:9]2([OH:30])[C:17]3[C:12](=[C:13]([F:19])[CH:14]=[CH:15][C:16]=3[F:18])[C:11](=[O:20])[N:10]2[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]#[CH:28])[C:22]=2[F:29])[CH:5]=[CH:6][C:7]=1[NH2:8].[CH3:31][O:32][C:33]([NH:35][C:36](=NC(OC)=O)SC)=[O:34].[OH-].[Na+]>C(O)(=O)C>[CH3:31][O:32][C:33](=[O:34])[NH:35][C:36]1[NH:8][C:7]2[CH:6]=[CH:5][C:4]([C:9]3([OH:30])[C:17]4[C:12](=[C:13]([F:19])[CH:14]=[CH:15][C:16]=4[F:18])[C:11](=[O:20])[N:10]3[C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]#[CH:28])[C:22]=3[F:29])=[CH:3][C:2]=2[N:1]=1

Participants

5

Reactant 3

HCID 14798Sodium HydroxideHCID 98708Methyl [[(methoxycarbonyl)amino](methylthio)methylene]carbamateHCID 86617515HCID 86617515, compound

Product 1

HCID 178436355HCID 178436355, compoundYield 83.4%

Reagents, catalysts & solvents 1

HCID 176Acetic AcidSolvent

Procedure

A solution of 3-(3,4-diaminophenyl)-2-(3-ethynyl-2-fluorophenyl)-4,7-difluoro-3-hydroxy-2,3-dihydro-1H-isoindol-1-one (1.15 g, 2.80 mmol) and 1,3-bis(methoxycarbonyl)-2-methyl-2-thiopseudourea (0.58 g, 2.80 mmol) was heated to 80° C. for 30 minutes in glacial acetic acid (15.0 mL). The reaction mixture was cooled to room temperature and it was pored into ice water. The pH was adjusted to 8 by the addition of 2M aqueous sodium hydroxide. The precipitated product was extracted with ethyl acetate (350 mL) and the organic layer was washed with brine and dried over anhydrous sodium sulfate. Filtration and evaporation resulted in a crude product. It was purified by reverse phase preparative HPLC (CH3CN/25 mM aqueous ammonium acetate). The fractions were collected, and the solvent was concentrated. The residue was partitioned with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, brine and dried over anhydrous sodium sulfate. Filtration and concentration resulted in an amorphous residue, which was freeze-dried from a mixture of acetonitrile-water (35.0 mL) to give methyl{5-[2-(3-ethynyl-2-fluorophenyl)-4,7-difluoro-1-hydroxy-3-oxo-2,3-dihydro-1H-isoindol-1-yl]-1H-benzimidazol-2-yl}carbamate (1.15 g, 83% yield). 1H NMR (400 MHz, CD3OD): 7.79 (s, 1H), 7.50 (d, J=8.4 Hz, 1H), 7.43-7.36 (m, 4H), 7.31 (t, J=7.2 Hz, 1H), 7.07 (t, J=7.6 Hz, 1H), 3.92 (s, 3H), 3.78 (s, 1H); MS (EI) for C25H15F3N4O4: 493 (MH+).

Workup

  1. extractionThe precipitated product was extracted with ethyl acetate (350 mL)
  2. washthe organic layer was washed with brine
  3. dry with materialdried over anhydrous sodium sulfate
  4. filtrationFiltration and evaporation
  5. customresulted in a crude product
  6. customIt was purified by reverse phase preparative HPLC (CH3CN/25 mM aqueous ammonium acetate)
  7. customThe fractions were collected
  8. concentrationthe solvent was concentrated
  9. customThe residue was partitioned with ethyl acetate
  10. washThe organic layer was washed with saturated aqueous sodium bicarbonate, brine
  11. dry with materialdried over anhydrous sodium sulfate
  12. filtrationFiltration and concentration
  13. customresulted in an amorphous residue, which
  14. dry with materialwas freeze-dried from a mixture of acetonitrile-water (35.0 mL)

Sources & evidence

ORD record
ord-e1e8d5f1b2394c5683e22fa299c4db1d
Source dataset
uspto-grants-2014_04
Patent number
US08697737B2

Reaction notes

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